Emerging and re-emerging pathogens such as HIV, prions, MRSA, XDR Tb, West Nile, hendra- and nipah, metapneumo-, calici-, hanta-, Ebola-, Marburg-, corona-, influenza-, chikungunya- and rhinoviruses, are sculpting a new landscape for public health and clinical medicine. This phenomenon has been ascribed to the destruction of natural habitats;political instability and poverty;climate change;the increased susceptibility to infection of an aging population or one immunosuppressed by HIV, cancer or transplantation;increasing population density;and inappropriate use of antibiotics. With globalization of travel and trade, microbes, vectors and reservoirs do not remain geographically discrete. Point source infections can rapidly become outbreaks or distribute even more broadly to become pandemics. Thus, clinicians and public health practitioners must be prepared for the appearance of new pathogens, new syndromes, as well as known syndromes due to known pathogens in new contexts. Classical culture techniques, immunohistochemistry, EM, and serology are vital in pathogen discovery as well as diagnostic clinical microbiology; nonetheless, molecular methods are increasingly employed due to speed, lower cost and the capacity to succeed in instances where fastidious requirements confound cultivation. We have established a staged strategy that enables rapid identification of emerging as well as known pathogens. This strategy will be used to investigate unexplained hemorrhagic fevers, unexplained encephalitis and meningoencephalitis, and unexplained febrile illness in "hot spots" in Asia, Africa and South America using materials collected from well characterized subjects under standardized network protocols. Specific Aims include: (1) Optimize preparation of nucleic acid template for GreeneChip and high throughput sequencing platforms;(2) Investigate unexplained hemorrhagic fevers;(3) Investigate unexplained encephalitis and meningoencephalitis;(4) Investigate unexplained febrile illness;and (5) Investigate potential reservoirs and vectors for the presence of agents implicated in Aims 2-4.